1-119735333-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_006623.4(PHGDH):c.682G>T(p.Gly228Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,614,216 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G228E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

PHGDH
NM_006623.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3O:1

Conservation

PhyloP100: 9.49

Publications

8 publications found

Variant links:

Genes affected

PHGDH (HGNC:8923): (phosphoglycerate dehydrogenase) This gene encodes the enzyme which is involved in the early steps of L-serine synthesis in animal cells. L-serine is required for D-serine and other amino acid synthesis. The enzyme requires NAD/NADH as a cofactor and forms homotetramers for activity. Mutations in this gene have been found in a family with congenital microcephaly, psychomotor retardation and other symptoms. Multiple alternatively spliced transcript variants have been found, however the full-length nature of most are not known. [provided by RefSeq, Aug 2011]

PHGDH Gene-Disease associations (from GenCC):

neurometabolic disorder due to serine deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
PHGDH deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
Neu-Laxova syndrome 1
Inheritance: AR Classification: MODERATE Submitted by: G2P
Neu-Laxova syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PHGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 1-119735333-G-T is Benign according to our data. Variant chr1-119735333-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 581769.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0015 (2196/1461868) while in subpopulation NFE AF = 0.00183 (2037/1112002). AF 95% confidence interval is 0.00177. There are 5 homozygotes in GnomAdExome4. There are 1056 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006623.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHGDH	NM_006623.4	MANE Select	c.682G>T	p.Gly228Trp	missense	Exon 7 of 12	NP_006614.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHGDH	ENST00000641023.2	MANE Select	c.682G>T	p.Gly228Trp	missense	Exon 7 of 12	ENSP00000493175.1	O43175
PHGDH	ENST00000369409.9	TSL:1	c.682G>T	p.Gly228Trp	missense	Exon 7 of 12	ENSP00000358417.5	A0A2C9F2M7
PHGDH	ENST00000641597.1		c.682G>T	p.Gly228Trp	missense	Exon 10 of 15	ENSP00000493382.1	O43175

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00145

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000845

AC:

212

AN:

250914

AF XY:

0.000767

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00150

AC:

2196

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1056

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00183

AC:

2037

AN:

1112002

Other (OTH)

AF:

0.00109

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

127

254

381

508

635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000866

AC:

132

AN:

152348

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41594

American (AMR)

AF:

0.000915

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000799

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

PHGDH deficiency (3)

Neu-Laxova syndrome 1 (1)

not provided (1)

not specified (1)

PHGDH-related disorder (1)

PHGDH deficiency;C4551478:Neu-Laxova syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.73

MetaRNN

Uncertain

0.51

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

4.1

PhyloP100

9.5

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MVP

0.94

MPC

0.97

ClinPred

0.67

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.96

gMVP

0.80

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over